10-Second heart rate variability and

cognitive function in old age

Simin Mahinrad, MD,

MSc
J. Wouter Jukema, MD,
PhD
Diana van Heemst, PhD
Peter W. Macfarlane,
MD, PhD
Elaine N. Clark, MA
Anton J.M. de Craen,
PhD
Behnam Sabayan, MD,
PhD

Correspondence to
Dr. Sabayan:
b.sabayan@lumc.nl

ABSTRACT

Objective: To investigate the cross-sectional and longitudinal associations of 10-second heart

rate variability (HRV) with various domains of cognitive function in older participants at risk of cardiovascular disease.

Methods: We studied 3,583 participants, mean age of 75.0 years, who were enrolled in the Prospective Study of Pravastatin in the Elderly at Risk. From baseline 10-second ECGs, standard
deviation of normal-to-normal intervals was calculated as the index of HRV. Four cognitive
domains were assessed at baseline and repeated during a mean follow-up period of 3.2 years.
Results: Lower HRV at baseline was associated with worse performance in reaction time (mean
difference between low third vs high third of HRV 5 1.96 seconds, 95% confidence interval
[CI] 0.20 to 3.71) and processing speed (20.57 digits coded, 95% CI 21.09 to 20.05). During
follow-up, participants with lower HRV had a steeper decline in processing speed (mean annual
change between low third vs high third of HRV 5 20.16 digits coded, 95% CI 20.28 to 20.04).
There was no difference in annual changes of reaction time or immediate and delayed memory
among HRV thirds during follow-up. All these associations remained unchanged after adjustment
for medications, cardiovascular risk factors, and comorbidities.

Conclusions: Participants with lower 10-second HRV have worse performance in reaction time
and processing speed and experience steeper decline in their processing speed, independent
of medications, cardiovascular risk factors, and comorbidities. Neurology 2016;86:11201127
GLOSSARY
HRV 5 heart rate variability; MMSE 5 Mini-Mental State Examination; PROSPER 5 Prospective Study of Pravastatin in the
Elderly at Risk; SDNN 5 standard deviation of normal-to-normal R-R intervals.

Supplemental data
at Neurology.org

Heart rate variability (HRV), the variation in consecutive heartbeat intervals, results from the
constant interaction between the sympathetic and parasympathetic arms of the autonomic nervous system.1 Reduced HRV is shown to be a strong predictor of cardiovascular morbidity and
mortality2,3 and has been linked to several vascular risk factors such as hypertension, diabetes
mellitus, and subclinical inflammation.4
Current evidence indicates that vascular risk factors are independently associated with cognitive impairment in older participants. Cardiovascular risk factors and morbidities contribute to
the development of cognitive impairment possibly by affecting the neurovascular integrity of the
brain.5 Neurovascular integrity of the brain is dependent on adequate and constant cerebral
blood flow and regulation of cerebral blood flow requires intact function of autonomic nervous
system.5,6 Hence, participants with lower HRV, as a reflection of autonomic dysfunction, might
be at increased risk of cognitive decline.
HRV is typically measured using long- or short-term ECG recordings. Long-term measurements provide detailed information during physiologic conditions such as activity and rest.
Despite merits of long-term measurements, they are time-consuming and involve patient discomfort, which might limit their application in routine clinical practice. On the other hand,
measuring HRV from a 10-second ECG recording is more practical and easier to apply in daily
Deceased.
From the Departments of Gerontology and Geriatrics (S.M., D.v.H., A.J.M.d.C., B.S.), Cardiology (J.W.J.), and Radiology (B.S.), Leiden
University Medical Center, the Netherlands; and Institute of Cardiovascular and Medical Science (P.W.M., E.N.C.), University of Glasgow, UK.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

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practice. It has been suggested that 10-second

HRV may predict 5-minute cardiac vagal
tones accurately7 and has a comparable predictive value for cardiac mortality in older
participants.8 However, to date there is no
study evaluating the association of HRV with
cognitive function using 10-second HRV
measurements.
In this study, we assessed the cross-sectional
and longitudinal association of HRV, using
10-second ECG recordings, with various domains of cognitive function in older participants at high risk of cardiovascular disease.
METHODS Study design. The data for this study were
drawn from the Prospective Study of Pravastatin in the Elderly
at Risk (PROSPER), a large prospective study of 5,804 men
and women aged 7082 years. PROSPER was a randomized
controlled trial designed to examine the effect of pravastatin in
older participants with preexisting or at high risk of cardiovascular
diseases. The mean follow-up time was 3.2 years. The PROSPER
study design and inclusion and exclusion criteria have been
described elsewhere.9,10

Standard protocol approvals, registrations, and patient

consents. We received approval from the institutional ethics
review boards of the 3 centers on human experimentation and
the PROSPER study complied with the Declaration of Helsinki.
All participants in the study provided written informed consent.10

Study participants. In this study, we excluded all participants

with cardiac arrhythmias or cardiac rhythms not generated by
the sinoatrial node, including premature ventricular or atrial contractions (n 5 414), ectopic atrial rhythm (n 5 161), supraventricular arrhythmia (n 5 139), atrial fibrillation (n 5 89), atrial
flutter (n 5 13), and other arrhythmias (n 5 85), from the
original PROSPER cohort. Individuals with sinus arrhythmia
were also excluded (n 5 314). Furthermore, participants with
missing HRV measurements at baseline (n 5 148) and with
missing cognitive measurements at baseline or during follow-up
(n 5 858) were excluded. Accordingly, 3,583 participants were
included in this study. Included participants were slightly
younger and had lower degrees of cardiovascular comorbidities
(table e-1 on the Neurology Web site at Neurology.org). We
included participants from both pravastatin and placebo groups
as it has been shown that treatment with pravastatin does not
affect cognitive function.11 Moreover, we adjusted our analyses
for pravastatin treatment groups.

HRV measurements. Standard 10-second ECG recordings

were obtained in resting, supine position using a Burdick
Eclipse 850i electrocardiograph in the morning of the first
enrollment visit before initiation of statin treatment. These
digital data were subsequently transferred to the University of
Glasgow ECG Core Lab based at Glasgow Royal Infirmary,
Scotland, for storage.12 HRV was measured using the
University of Glasgow resting ECG programa fully
automated methodto ensure the reproducibility of the
measurements and interpreted using the same software.13 We
used one of the most frequently used and easily calculated time
domain measurements of HRV defined as the standard deviation
of normal-to-normal R-R intervals (SDNN) in the 10-second

ECG recording period. For each ECG, the onset of every QRS
complex was recorded and then the dominant or normal-tonormal R-R intervals were calculated. Dominant R-R intervals
are defined as the time between 2 normally conducted QRS
complexes. The standard deviation of dominant R-R intervals
was calculated thereafter.

Cognitive function measurements. The Mini-Mental State

Examination (MMSE) was used to measure global cognitive
function at baseline. The cutoff point of 24 or more was applied
as the inclusion criterion and participants with poor cognitive
function (MMSE , 24) were excluded from enrollment in
PROSPER. In this study, we used 4 neuropsychological
performance tests to assess different domains of cognitive
function. The Stroop test was used to assess selective attention
and reaction time. The outcome variable was the time (number
of seconds) taken to complete the test, with higher scores
indicating worse performance. The Letter-Digit Coding test was
used to measure the general cognitive processing speed. The
outcome variable was the total number of correct digits entered
in 60 seconds; a higher score indicates better performance.
Memory was assessed using the Picture-Word Learning Test,
which tests immediate and delayed memory. The outcome
variable was the accumulated number of correctly recalled
pictures over 3 trials and the number of pictures recalled during
delayed recall; a higher score indicates better performance. The
test/retest correlation of Stroop and Letter-Digit Coding tests were
shown to be high (r 5 0.80 and 0.88, respectively). The reliability
of immediate and delayed Picture-Word Learning tests were
shown to be acceptable (r 5 0.66 and 0.63, respectively). In
addition, the test/retest correlations were independent of age and
education.14 Cognitive function was measured at baseline, after 9,
18, and 30 months, and at the end of the study. The time point at
the end of the study varied among participants and ranged from 36
to 48 months.
Statistical analyses. Baseline characteristics of participants are
reported as mean (SD) for continuous variables and as number
of participants (%) for categorical variables across thirds of HRV.
To test the cross-sectional and longitudinal association of
HRV and cognitive domains, we used linear regression models.
In longitudinal analyses, regression coefficient of the change in
each cognitive test score per year was calculated for each participant, which indicates the annual changes in cognitive domains
during follow-up time. This allowed us to test the longitudinal
associations more accurately by using repeated measurements of
cognitive tests. In both cross-sectional and longitudinal analyses,
probability values were calculated using continuous logtransformed values of baseline SDNN as the determinant, since
it was not normally distributed. Using analysis of covariance,
we calculated the adjusted mean values of baseline and annual
changes of cognitive scores in thirds of HRV.
All cross-sectional and longitudinal analyses were performed
in 2 steps. In the first step (minimally adjusted model), the analyses were adjusted for age, sex, education (age at which the participants left school), country of enrollment, and version of
cognitive tests where appropriate. In the second step (fully
adjusted model), the analyses were further adjusted for cardiovascular risk factors and comorbidities and use of antihypertensive
medications. In the longitudinal analyses, both models were additionally adjusted for baseline cognitive domain scores, and the
fully adjusted model was additionally adjusted for statin
treatment.
To explore the effect of cardiovascular events on the longitudinal associations, we performed a series of additional analyses in
which we stratified for participants who did and did not develop
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incident stroke, incident heart failure hospitalization, and incident coronary events. To test whether the difference between participants who did and did not develop cardiovascular events is
significant, p value for interaction was calculated using linear
regression models.
To test whether the association of HRV with cognitive domains is independent of b-blockers and medications with antiarrhythmic or anticholinergic properties, the longitudinal analyses
were repeated after exclusion of participants who used those medications. Finally, to check whether the relation between HRV and
cognitive domains is independent of heart rate, the cross-sectional
and longitudinal analyses were repeated after standardizing HRV
for heart rate (SDNN was divided by heart rate).15 A p value of
,0.05 was considered as statistically significant.

The mean age of the study population was

75.0 years and 1,675 (46.7%) participants were male.
Median HRV as measured by SDNN was 17.00 ms.
Table 1 shows the baseline characteristics of participants in thirds of HRV. Participants in the lowest third
of HRV were older, had higher resting heart rate, had
higher body mass index, and used b-blockers less frequently (all p values ,0.05).
Table 2 shows the cross-sectional association of
HRV with cognitive domains in the minimally
adjusted model. At baseline, participants with lower
HRV had worse performance on the Stroop test
(mean score of 64.71 seconds in the lowest third,
64.46 seconds in the middle third, and 62.75 seconds
RESULTS

Table 1

in the highest third, p 5 0.008) and the Letter-Digit

Coding test (mean score of 23.62 digits coded in the
lowest third, 23.67 digits coded in the middle third,
and 24.18 digits coded in the highest third, p 5
0.008). Lower HRV was not associated with worse
performance in the immediate and delayed PictureWord Learning tests. Figure 1 shows the crosssectional association of HRV with cognitive domains
after full adjustment for medications, cardiovascular
risk factors, and comorbidities. Full adjustments did
not change the cross-sectional results, meaning that
lower HRV remained associated with worse performance in the Stroop and Letter-Digit Coding tests.
Table 3 shows the association of baseline HRV
and changes in cognitive domains during a mean
follow-up of 3.2 years. In the minimally adjusted
model, participants with lower HRV had a steeper
decline in the Stroop test performance (mean annual
change of 1.63 seconds in the lowest third, 0.96 seconds in the middle third, and 1.11 seconds in the
highest third), although this association was marginal
(p 5 0.073). Similarly, participants with lower HRV
had a steeper decline in the Letter-Digit Coding test
score (mean annual change of 20.50 digits coded in
the lowest third, 20.49 digits coded in the middle
third, and 20.35 digits coded in the highest third,
p 5 0.016). In contrast, low HRV was not associated

Baseline characteristics of participants in thirds of heart rate variability

Thirds of SDNN, ms
Low (1.7012.60)
(n 5 1,197)

Middle (12.7022.90)
(n 5 1,193)

High (23.00128.40)
(n 5 1,193)

75.24 (3.38)

74.98 (3.25)

74.92 (3.28)

0.047

Male, n (%)

553 (46.2)

563 (47.2)

559 (46.9)

0.885

Age left school, y, mean (SD)

15.23 (2.09)

15.24 (2.14)

15.15 (2.11)

0.507

,0.001

Characteristics

p Value

Sociodemographics
Age, y, mean (SD)

Cardiovascular risk factors

HR, beats/min, mean (SD)

70.01 (11.71)

64.80 (10.40)

61.71 (9.80)

History of stroke or TIA, n (%)

136 (11.4)

131 (11.0)

106 (8.9)

0.103

History of MI, n (%)

146 (12.2)

140 (11.7)

153 (12.8)

0.718

History of DM, n (%)

143 (11.9)

127 (10.6)

108 (9.1)

0.070

SBP, mm Hg, mean (SD)

155.87 (21.4)

154.52 (22.8)

153.17 (21.3)

0.010

DBP, mm Hg, mean (SD)

84.6 (11.0)

84.0 (11.6)

82.6 (10.8)

BMI, kg/m , mean (SD)

27.21 (4.2)

26.83 (4.1)

26.74 (4.0)

0.015

Current smoking, n (%)

286 (23.9)

325 (27.2)

323 (27.1)

0.110

,0.001

Antihypertensive medications
b-Blockers, n (%)

283 (23.6)

337 (28.2)

366 (30.7)

,0.001

Calcium channel blockers, n (%)

303 (25.3)

303 (25.4)

301 (25.2)

0.996

Abbreviations: BMI 5 body mass index; DBP 5 diastolic blood pressure; DM 5 diabetes mellitus; HR 5 heart rate; MI 5
myocardial infarction; SBP 5 systolic blood pressure; SDNN 5 standard deviation of normal-to-normal R-R intervals.
The differences in characteristics across thirds of SDNN were examined using analysis of variance test for continuous
variables and x2 test for categorical variables.
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Table 2

Baseline cognitive domains in relation to heart rate variability

Thirds of SDNN, ms
Low (1.7012.60)
(n 5 1,197)

Cognitive test

Middle (12.7022.90)
(n 5 1,193)

High (23.00128.40)
(n 5 1,193)

p Valuea

Stroop, s

64.71 (0.63)

64.46 (0.63)

62.75 (0.63)

0.008

LDCT, digits coded

23.62 (0.19)

23.67 (0.19)

24.18 (0.19)

0.008

PLTi, pictures remembered

9.44 (0.05)

9.38 (0.05)

9.47 (0.05)

0.353

PLTd, pictures remembered

10.28 (0.07)

10.26 (0.07)

10.41 (0.07)

0.130

Abbreviations: LDCT 5 Letter-Digit Coding Test; PLTd 5 Picture-Word Learning Test delayed; PLTi 5 Picture-Word Learning Test immediate; SDNN 5 standard deviation of normal-to-normal R-R intervals.
Data represent mean score (standard error) of each cognitive test. Adjusted for country, age, sex, education, and version of
LDCT and PLT tests.
a
The p values were calculated using the continuous values of log-transformed SDNN.

with accelerated decline in the immediate and delayed

Picture-Word learning test scores during follow-up.
After full adjustment for cardiovascular risk factors,
comorbidities, and use of medications, the estimates
of the difference in cognitive domains between the
HRV groups did not change essentially. Lower
HRV remained associated with a steeper decline in
the Letter-Digit coding test score (p 5 0.038),
whereas for the Stroop test and the immediate and
delayed Picture-Word learning tests, the associations
did not reach statistical significance (p 5 0.084,
0.337, and 0.738, respectively). In additional analyses,

Figure 1

we combined the lowest and the middle thirds of

HRV and repeated the cross-sectional and longitudinal analyses. Results show that compared to the high
HRV group, the combined middle and low HRV
group was associated with worse performance on the
Stroop and the Letter-Digit Coding tests (table e-2).
The longitudinal results indicate that the combined
middle and low HRV thirds is associated with a
steeper decline on the Letter-Digit Coding test and
the immediate Picture-Word Learning test (table e-3).
Figure 2 shows the association of HRV with cognitive decline stratified by cardiovascular events

Baseline cognitive domains in relation to heart rate variability (HRV) in the fully adjusted model

Bars represent mean and standard errors. All analyses were adjusted for country, age, sex, education, version of Letter-Digit
Coding Test (LDCT) and Picture-Word Learning Test (PLT), body mass index, smoking, systolic blood pressure, diastolic blood
pressure, history of stroke/TIA, history of myocardial infarction, history of diabetes mellitus, and antihypertensive medications (diuretics, b-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor
blockers). PLTd 5 Picture-Word Learning Test delayed; PLTi 5 Picture-Word Learning Test immediate; SDNN 5 standard
deviation of normal-to-normal R-R intervals.
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Table 3

Annual changes in cognitive domains in relation to heart rate variability

Thirds of SDNN

Cognitive tests

Low (1.7012.60)
(n 5 1,197)

Middle (12.7022.90)
(n 5 1,193)

High (23.00128.40)
(n 5 1,193)

p Valuea

Stroop, s
Minimally adjusted model

1.63 (0.30)

0.96 (0.30)

1.11 (0.30)

0.073

Fully adjusted model

1.62 (0.30)

0.94 (0.30)

1.13 (0.30)

0.084

Minimally adjusted model

20.50 (0.04)

20.49 (0.04)

20.35 (0.04)

0.016

Fully adjusted model

20.50 (0.04)

20.49 (0.04)

20.35 (0.04)

0.038

Minimally adjusted model

20.06 (0.02)

20.05 (0.02)

20.01 (0.02)

0.257

Fully adjusted model

20.06 (0.02)

20.05 (0.02)

20.01 (0.02)

0.337

Minimally adjusted model

20.11 (0.03)

20.10 (0.03)

20.09 (0.03)

0.698

Fully adjusted model

20.11 (0.03)

20.10 (0.03)

20.10 (0.03)

0.738

LDCT, digits coded

PLTi, pictures remembered

PLTd, pictures remembered

Abbreviations: LDCT 5 Letter-Digit Coding Test; PLTd 5 Picture-Word Learning Test delayed; PLTi 5 Picture-Word Learning Test immediate; SDNN 5 standard deviation of normal-to-normal R-R intervals.
Data represent mean annual change (standard error) in each cognitive test. Minimally adjusted model: adjusted for country,
age, sex, education, cognitive scores at baseline, and version of LDCT and PLT tests. Fully adjusted model: adjusted for
country, age, sex, education, baseline cognitive scores, version of LDCT and PLT tests, body mass index, smoking, systolic
blood pressure, diastolic blood pressure, history of stroke/TIA, history of myocardial infarction, history of diabetes mellitus,
statin treatment, and antihypertensive medications (diuretics, b-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers).
a
The p values were calculated using the continuous values of log-transformed SDNN.

during follow-up, including stroke or TIA (n 5 199),

heart failure hospitalization (n 5 78), and (3) coronary events (n 5 269). There was no difference in
change of cognitive domains during follow-up
between participants who did and did not develop
cardiovascular events (all p for interaction .0.05).
Likewise, stratification of participants based on the
presence of history of stroke or TIA at baseline did
not change the longitudinal results (data not shown).
Furthermore, the sensitivity analyses after exclusion of participants who used b-blockers (n 5 986)
and medications with antiarrhythmic (n 5 75) or
anticholinergic (n 5 98) properties did not change
the associations between HRV and cognitive decline
(table e-4). After exclusion of participants who used
b-blockers (n 5 986, 27.5% of the population), the
association between HRV and Letter-Digit Coding
test scores remained essentially the same, with marginal p values (table e-4). Finally, standardization of
SDNN for heart rate did not change the crosssectional and longitudinal results (tables e-5 and e-6).
In this study, we show that older
participants at risk of cardiovascular disease with
lower 10-second HRV have worse performance
on reaction time and processing speed and
experience steeper decline in their processing
speed during a mean period of 3.2 years. These
DISCUSSION

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Neurology 86

associations were independent of cardiovascular

risk factors and comorbidities.
Our findings are in line with some studies on the
association between HRV and cognitive function. For
example, cross-sectional results from 869 Mexican
Americans with mean age of 75 years have shown that
reduced 5-minute HRV was associated with worse
performance on the MMSE test, but not with verbal
memory.16 Results from the Vietnam Era Twin Registry on healthy middle-aged men showed that
reduced 24-hour HRV was associated with poor verbal but not visual and memory performance.17 The
cross-sectional results from the Irish Longitudinal
Study on Ageing (TILDA) showed that reduced
5-minure HRV was most strongly associated with
worse performance in memory recall and language.18
To date, the only prospective study on the longitudinal association between HRV and cognitive function
is the UK Whitehall II study, which showed no crosssectional or longitudinal associations.19 However, in
that study, the cognitive battery used was not able to
assess the executive function in details. Furthermore,
their population consisted of middle-aged adults who
were much younger than the PROSPER participants.
There are several explanations for the observed associations between HRV and cognitive function.
First, cardiovascular risk factors such as hypertension,
subclinical inflammation, and diabetes mellitus have

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2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Figure 2

Annual changes in cognitive domains in relation to heart rate variability (HRV), stratified for
cardiovascular events during follow-up

Data represent annual change (95% confidence interval [CI]) per 1 millisecond increase in log-transformed standard deviation of normal-to-normal R-R interval for each cognitive test, stratified by cardiovascular events during follow-up. Adjusted
for country, age, sex, education, version of Letter-Digit Coding Test (LDCT) and Picture-Word Learning Test (PLT), body
mass index, smoking, systolic blood pressure, diastolic blood pressure, history of stroke/TIA, history of myocardial infarction, history of diabetes mellitus, statin treatment, and antihypertensive medications (diuretics, b-blockers, calcium channel
blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers). The p values show p for interaction.
HF 5 heart failure.

been linked to both reduced HRV and cognitive

impairment.4,20,21 This might suggest that cardiovascular risk factors play role as extraneous factors on the
association between HRV and cognitive function.
Nevertheless, we observed that adjustment of our
analyses for several well-established cardiovascular
risk factors did not change the associations. Second,
reduced HRV is associated with future cardiovascular
events,3,22 which in turn might result in neurocognitive deficits and cognitive decline. We observed that
the association between HRV and cognitive function
was not different in participants without cardiovascular events during the follow-up time. In this setting,
reduced HRV might serve as an early manifestation of
brain damage mirrored in disturbed autonomic nervous system. Third, low HRV as a reflection of autonomic dysfunction might directly link to cognitive
impairment by causing dysregulations in cerebral perfusion.23 Furthermore, it is possible that lower HRV

might reflect established cerebral lesions and neurodegenerative processes in the brain.18 Finally, given
that low HRV have been associated with higher blood
pressure variability24 and that higher blood pressure
variability has been shown to be associated with cognitive decline and structural brain changes,25,26 it is
likely that altered HRV is associated with cognitive
decline by increasing blood pressure variability.
In this study, we show that reduced HRV is
related to worse performance and future decline of
executive function. Executive function is mainly controlled by the prefrontal cortex of the brain. It has
been shown that reduced HRV is associated with hypoactivity of the prefrontal cortex, which might in
turn disturb executive function.27,28 In a metaanalysis, Thayer et al.29 showed that HRV is closely
related to neuronal activities in the ventromedial prefrontal cortex. Furthermore, it has been shown that
the frontal cortex is able to adjust HRV via
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subcortical structures such as the amygdala. This

cortico-subcortical inhibitory circuit is the structural
connection between neuropsychological processes
such as cognitive function and physiologic processes
such as HRV. Abnormalities in the corticosubcortical circuit can be reflected in HRV.28 In this
setting, future brain imaging studies might bring new
insights in the biology of observed associations.
The selective association of lower HRV with cognitive domains involving speed needs further exploration. Previously, it has been shown that the
detrimental effects of cardiovascular risk factors are
more evident in such cognitive domains30; however,
it is also possible that HRV is basically related to the
pace of performing a certain task and not necessarily
to the cognitive ability of the participants. In addition, we observed that the largest changes in cognitive
scores were between the high HRV group and the
remaining two-thirds of the population. It is important to mention that there is no well-established clinical cutoff value for categorization of HRV indices,
which might hamper grouping of participants, and
therefore the comparisons should be performed
cautiously.
This study has certain strengths and limitations.
The major strengths are the large sample size and
the prospective design, which allowed us to examine
the temporality of associations. Furthermore, we used
an extensive set of neuropsychological tests consisting
of 4 cognitive tests to assess different domains of cognitive function. We could also show that the results
are independent of cardiovascular risk factors and comorbidities. As limitations, the participants in this
study were at high risk of cardiovascular disease,
which makes it difficult to generalize our findings
to a healthy elderly population. Nevertheless, a considerable proportion of older adults have a number
of cardiovascular pathologies and our results were
independent of cardiovascular risk factors, comorbidities, and use of medications. Using a 10-second
HRV might serve as a possible limitation as it does
not allow capturing the circadian changes. However,
we were able to show that reduced HRV associates
with cognitive impairment even by using 10-second
HRV, which is widely used in clinical practice and
is more feasible for assessment. Another limitation
could be the relatively small changes in the absolute
scores of cognitive domains. This might be due to
the PROSPER inclusion criteria (MMSE $ 24
points) resulting in participants with relatively preserved cognitive function at baseline. Of note,
although the magnitude of associations was modest,
the effect estimates were comparable with the effect
estimates of APOE4 in the same population.31
In our cohort of older participants at high risk
of cardiovascular disease, participants with lower
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10-second HRV have worse performance in reaction

time and processing speed and experience steeper
decline in their processing speed, independent of cardiovascular risk factors and comorbidities.
AUTHOR CONTRIBUTIONS
S. Mahinrad contributed to the study concept and design, drafting the
manuscript, data interpretation, critical revision of the manuscript for
important intellectual content, and statistical analyses. J. Wouter Jukema,
Peter W. Macfarlane, and Elaine N. Clark contributed to acquisition of
data, data interpretation, and critical revision of the manuscript for
important intellectual content. Diana van Heemst contributed to data
interpretation and critical revision of the manuscript for important intellectual content. A.J.M. de Craen contributed to data interpretation and
critical revision of the manuscript for important intellectual content, statistical analyses, and study supervision. B. Sabayan contributed to study
concept and design, data interpretation, critical revision of the manuscript
for important intellectual content, statistical analyses, and study supervision. Dr. B. Sabayan had full access to all the data and takes responsibility
for the data, accuracy of the data analysis, and the conduct of the
research.

STUDY FUNDING
The original PROSPER clinical trial was funded by an investigatorinitiated grant from Bristol-Myers Squibb, USA. The company had no
involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and
approval of the manuscript; or decision to submit the manuscript for
publication. B. Sabayan is partly supported by a grant from Internationale
Stichting Alzheimer Onderzoek (ISAO).

DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.

Received August 11, 2015. Accepted in final form December 8, 2015.

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10-Second heart rate variability and cognitive function in old age

Simin Mahinrad, J. Wouter Jukema, Diana van Heemst, et al.
Neurology 2016;86;1120-1127 Published Online before print February 17, 2016
DOI 10.1212/WNL.0000000000002499
This information is current as of February 17, 2016
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